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p38-MAPK inhibition and endotoxin induced tubular dysfunction in men

Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands

Jaap E. Tulleken

Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands, j.e.tulleken{at}int.azg.nl

Jack J.M. Ligtenberg

Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands

Peter de Boer

R. W. Johnson Pharmaceutical Research Institute, Bassersdorf, Switzerland

Tjip S. van der Werf

Intensive and Respiratory Care Unit, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands

Background: To evaluate the possibility of preventing endotoxin induced renal damage by p38-MAPK inhibition in a human model.

Design and Methods: Twenty-one healthy young male volunteers received 4 ng/kg Escherichia coli endotoxin as a single dose. Four groups of volunteers received an oral dose of placebo or 350, 700 or 1400 mg RWJ-67657, a p38-MAPK inhibitor, 20 min before endotoxin infusion. Urine samples were collected at set time intervals. The urinary excretion rate of ß₂-microglobulin and N-acetyl-ß-D-glucosaminidase, as indicators of tubular dysfunction was determined.

Results: There was a significant increase of ß₂-microglobulin and N-acetyl-ß-D-glucosaminidase urine excretion rate after endotoxin infusion in the placebo group. p38-MAPK inhibition prevented the increase of markers for tubulopathy.

Conclusions: Endotoxin infusion induces measurable tubular damage. Blocking the p38-MAPK may prevent this damage. The mechanism is unclear, but blocking TNF- release is a possible explanation.

Key Words: Endotoxin • renal failure • p38-MAPK inhibition • tubulopathy

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